Project Summary We propose that AXL, a receptor tyrosine kinase AXL (RTK), can be activated by ligand-independent manner through interaction with another RTK, MET, and form a heterodimeric AXL-MET complex to launch a unique signaling program for cancer cell migration and invasion. MET and AXL are two recently characterized oncogenic RTKs implicated in invasive cell growth and cancer cell migration. Emerging evidence indicates that aberrant activation and overexpression of AXL or gene amplification of MET confer a common resistance mechanism to targeted and conventional therapies in aggressive and metastatic cancers including glioblatoma multiforme (GBM), breast and lung carcinomas. Co-activation of AXL and/or MET with other RTKs such as EGFR or IGF-1R is also recognized as a major hindrance to targeted cancer therapies. The canonical activation of many RTKs involves the binding of a specific ligand to its cognate receptor to promote RTK homo-dimerization to launch a specific signaling cascade. We have recently found that HGF, a natural ligand for MET RTK, induces the activation of a different RTK, AXL, by promoting the formation of MET-AXL hetero-RTK complexes to trigger a novel downstream signaling cascade for cancer cell migration and invasion. Our findings on the formation of MET-AXL hetero-RTK complexes represent a novel and uncharacterized mechanism for activating RTKs. We propose to investigate this novel signaling process that present new targets for future therapies In this application, we will investigate the mechanism by which AXL is activated through interaction with MET to promote cancer cell motility, by conducting the following specific aims: Specific Aim 1. To determine the relationship between homo-RTK and hetero-RTK complexes Specific Aim 2. To identify the novel mechanism underlying the activation and signaling cascade of the MET-AXL hetero-RTK complex. Specific Aim 3. To determine the effects of selective depletion of the p140 form of AXL. As co-activation of RTKs is critically important in GBM and in a multitude of human cancers, elucidation of this new regulatory mechanism may provide novel targets for prevention and therapeutic treatment.